Antigen-independent formation of renal Trm-like CD8 T cells perpetuates hypertension 2259853

Abstract Introduction T cells critically contribute to hypertension, a condition affecting nearly half of American adults and driving cardiovascular mortality. However, the mechanisms by which these cells sustain hypertensive pathology remain unclear. We identified a persistent, memory-like CD8T cell population in the kidneys of hypertensive humans and hypothesize that kidney-resident memory CD8T cells (CD8Trm) establish a renal salt-retention memory that drives the chronic progression and recurrence of hypertension. Methods Kidneys from hypertensive patients and mice were analyzed. Trm-deficient mice (T cell-specific TGFβ receptor knockout; Tsp-TGFβR-KO) were used to assess the role of Trms in hypertension. Flow cytometry, single-cell metabolic profiling, and histopathology characterized renal immune populations. Mechanistic studies employed Rag2OT-I mice and ex vivo stimulation of CD8 T cells with ATP + TGFβ to test antigen-independent Trm formation and effects on distal nephron epithelial cells. Results Abundant renal CD8Trm were identified in both hypertensive patients and mice. In contrast, Tsp-TGFβR-KO mice showed blunted blood pressure in response to chronic hypertensive stimuli. In the salt-memory model, Tsp-TGFβR-KO mice developed initial hypertension but were protected from recurrence upon high-salt rechallenge, confirming Trm involvement in renal salt-retention memory. Renal CD8Trm formation occurred without antigen; Rag2OT-I mice without OVA exposure still generated P2X7+ CD8Trm, implicating ATP-driven CD8T-activation. Ex vivo ATP plus TGFβ treatment induced Trm formation with canonical markers, cytokine production, and distinct metabolic profiles. Co-culture with renal tubule cells enhanced sodium retention, linking immune activation to renal salt handling. Conclusion We identify a renal CD8Trm population that sustains hypertension through ATP+TGFβ-driven activation. This CD8Trm-salt axis anchors immune-hypertensive memory, offering a new immunological target to prevent hypertension recurrence. Funding Source NIH F31HL175932, AHA24PRE1198737, NIH T32 GM150536, NIH R01-HL146713, AHA 23TPA1076467 Topic Categories Immune Mechanisms of Human Disease (HUM)